Malignant melanoma (MM) is one of the most invasive human cancers with its relative resistance to conventional chemotherapy and radiotherapy; only a small percentage of patients demonstrated durable responses to immunotherapy. Thus, a personalized strategy is urgently needed to develop assays which may guide the individual patient in the selection of appropriate therapy. Discovery of predictive biomarkers for immunotherapy response is an important strategy to attain this objective, which is stated in Provocative Questions for this RFA. MicroRNAs (miRNA) are small non-coding RNAs which regulate gene expression. Altered miRNA expression in tumor cells are found in variety types of cancer and contribute to therapy resistance in some cancer. We recently found that miRNAs are involved in immune cell development and function, and that cell-free serum from MM patients contains MM-specific miRNAs, which may serve as biomarkers for MM early diagnosis and prognosis. This application is designed to test the hypothesis that different miRNA expression profiles can be detected, either in MM tumor or in therapeutic targeting T cells, between patients who are responsive and who are resistant to immunotherapy. These differences could be reflected in the serum, which can potentially serve as convenient, noninvasive biomarkers for prediction of response to immunotherapy. We will begin by identifying the tumor-specific (Aim 1) and T cell-specific (Aim 2) miRNA expression profiles between therapy-responsive and therapy-resistant patients using TaqMan TR-PCR arrays; then will define serum specific miRNAs. The results from the proposed pioneering studies may enable us to predict MM patients who will respond to immunotherapy, using tissue/serum miRNAs as biomarkers, and may also facilitate the development of new intervention strategies for increasing immunotherapy for MM.